WHAT'S UP DOC? Potential of gene therapy still to be realized

Thursday

Jan 3, 2019 at 2:58 PMJan 3, 2019 at 2:58 PM

Q: I have read about gene therapy on and off for years, but not much has seemed to happen lately. What is the future of gene therapy?

A: First, a bit of a disclaimer: some of my earliest research in medicine was in the field of gene therapy (for example, I was lead author on an article in the journal Gene Therapy way back in 1995), so this is a field in which I likely have some (positive) bias.

The human genome, the set of more than 3 billion nucleic acid base pairs (coded on the 23 chromosome pairs, so 46 chromosomes total) that make up our DNA, is the hereditary map that guides the makeup and function of our bodies. All of our genes (about 20,000 of which encode for necessary proteins), as well as huge numbers of base pairs that control production of these proteins and some that seem to have little or no function (some experts estimate only 25 percent of the genome is functional, although others estimate this to be as high as 80 percent), are included in the genome.

The human genome project, launched in 1990 and completed in 2003, successfully sequenced these base pairs, allowing all this data to be explored to identify genes (including the 1 to 2 percent of the genome that codes for proteins), regulatory DNA (that helps control production of these proteins), as well as the rest of the genome (including the parts that are not yet understood and which may actually play no active function).

There has certainly been huge progress. The genetic issues that contribute to the development of many diseases have been identified. Improvements in understanding how certain body functions work have opened up different therapeutic approaches. For example, better understanding of how our immune system functions has opened up different treatment approaches for many kinds of cancer, as well as for many autoimmune diseases and other conditions.

However, the scientific potential of the mapping of the human genome has not yet been completely realized. This is, in a large part, due to the limitations we have to be able to develop treatments to address many genetic disorders.

There has been a development that shows huge promise, called CRISPR/Cas 9 (usually called CRISPR , which stands for Clustered Regularly Interspaced Short Palindromic Repeats, for short and pronounced crisper):

Step one was to understand how CRISPR worked: CRISPR is part of many bacteria’s defense against attacks from viruses. When the bacteria kills off an invading virus it creates enzymes to slice and then scoop up the remains of the genetic code of the dead virus, "memorizing" this information by storing it in its own genome. When a virus attacks again in the future, it uses this info to produce an enzyme specific for the prior attacking viruses’ genetic codes (called Cas9, think of this like a catalogue of past enemies overcome) which is designed to specifically destroy this sequence of base pairs.

Step two was to learn how to utilize this mechanism to cause the creation of Cas9 enzymes specific for any desired genetic sequence (rather than against an attacking virus).

The third step was to utilize all this to cut out a desired a genetic sequence from a strand of DNA; for example, to cut out a gene which has an erroneous base pair in it (so the protein it codes for does not function correctly, the root cause for many genetic diseases). If the disease in question is treatable by simply cutting out the erroneous genetic sequence, this can be the last step needed.

The fourth step is to insert a desired genetic sequence (for example, the correct genetic code for the desired protein) exactly where the defective genetic sequence was removed. It is important to place the correct sequence exactly where the erroneous sequence was removed, since other parts of the genetic material in that region function to help control the timing and amount of the protein production.

From this description it should be evident that CRSIPR has amazing potential to treat many diseases:

Simply cutting out undesired genetic sequences may treat a disease. For example, HIV occurs when the HIV virus inserts into a patient’s genome. Cutting out part of this HIV insertion can prevent the disease from manifesting. This technique could also be used to attack an infecting organism (viral/bacterial/other), doing a similar job to what antibiotics do.

Cutting out an incorrect genetic sequence and inserting a correct sequence could possibly treat many genetic disorders. For example, sickle cell disease is caused by a mutation causing a defect in the hemoglobin gene (the 6th codon of the beta-chain gene has thymine substituting for adenine). If this incorrect genetic sequence is removed and replaced by the correct sequence in the patient’s bone marrow cells, they would produce normal hemoglobin and in essence be “cured” of their sickle cell disease. This technique could also be used in plants, for example to maximize certain nutritional aspects or to make them more resistant to disease, drought, etc.

Certain diseases might be prevented by addressing their mode of transmission; for example, mosquitoes (or other insects) that carry malaria (or other diseases) might be modified to prevent disease transmission (or even to minimize the number of these insects).

Many other possible uses (yes, start to think about Jurassic Park scenarios).

Of course there are concerns:

What if the genetic sequence cut out is not (only) the desired one, or if the inserted new sequence is not done correctly (inserted in the wrong place or with the wrong code); might the patient develop cancer (or some other condition)?Are there ethical concerns (might these techniques be used to create ‘designer’ babies)? Is there potential for other abuses as well?If this technology is used to modify insects, might the disruption of the food chain have unintended consequences?

The potential of CRISPR is already aggressively being researched. In 2018 there were almost 20,000 scientific publications looking at possible implications and uses of CRISPR (including use of this technology in animal models of human diseases). As with all discoveries, the potential benefits must be carefully balanced against the potential risks, and the technology must be used ethically and with a careful consideration of potential unintended consequences.